Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt

ABSTRACT

The present invention relates to processes for the manufacture of (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino)carbonyl]-pyrrol- 1 -yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt.

FIELD OF THE INVENTION

The present invention relates to processes for the manufacture of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methylphenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt.

BACKGROUND OF THE INVENTION

Cardiovascular disease and its associated maladies, dysfunctions andcomplications are a principal cause of disability and the chief cause ofdeath. One specific factor significantly contributing to thispathophysiologic process is atherosclerosis, which has been generallyrecognized as a leading health care problem both with respect tomortality and health care costs. Atherosclerosis is characterized by thedeposition of fatty substances, primarily cholesterol, resulting inplaque formation on the inner surface of the arterial wall anddegenerative change to the arteries.

It is now well established that cardiovascular disorders includingmyocardial infarction, coronary heart disease, hypertension andhypotension, cerebrovascular disorders including stroke, cerebralthrombosis and memory loss due to stroke; peripheral vascular diseaseand intestinal infarction are caused by blockage of arteries andarterioles by atherosclerotic plaque. Atherosclerotic plaque formationis multi-factorial in its production. Hypercholesterolemia, especiallyelevated levels of low-density lipoprotein cholesterol (LDL), is animportant risk factor for atherosclerosis and arteriosclerosis andassociated diseases.

The HMG-CoA reductase inhibitors (statins) have been used in reducingblood levels of LDL cholesterol. Cholesterol is produced via themevalonic acid pathway. Reducing the formation of mevalonic acid, aprecursor to cholesterol, leads to a corresponding decrease in hepaticcholesterol biosynthesis with a reduction in the cellular pool ofcholesterol. PCT Publication No. WO 2004/106299 discloses(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methylphenyl amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt, having the Formula I,

as an effective HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A)reductase inhibitor and thus is useful as hypolipidemic andhypocholesterolemic agent.

A procedure for the synthesis of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methylphenyl amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt is disclosed in WO 2004/106299. The aforementionedsynthetic route involves isolation and purification of intermediates ateach step of the process by column chromatography. However, the totaloverall yield is low, and the high cost of production render the processnot amenable to large scale manufacture.

SUMMARY OF THE INVENTION

In one aspect, herein are provided improved processes for themanufacture of compound of Formula I, described above, at a commercialscale.

In another aspect, herein are provided improved processes which avoidthe use of column chromatography as a purification method, and are costeffective and easily amenable to large-scale production.

In yet another aspect, herein are provided processes of making highpurity compound of Formula I with increased overall yield by employingreaction conditions that include various solvents and solventcombinations, temperature conditions, time period and work-up proceduresat each stage of the process. Also, in still another aspect, herein isprovided isolation of intermediates of high purity with superior yieldswithout resorting to purification by column chromatography at any stageof the process.

In still another aspect, herein are provided one-pot processes for theconversion of a particular dihydroxy compound to the desired calciumsalt of Formula I in the final step, thus making the processes moreeconomical.

As discussed, herein are provided processes for the preparation of acompound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compound of Formula I,(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calciumsalt can be prepared by, for example, the following reaction sequence asdepicted in Scheme I.

Thus, the amine of Formula II when reacted withmethyl-4-methyl-3-oxopentanoate in refluxing hydrocarbon solvent canresult in a β-ketoamide of Formula IV (wherein R is aryl, alkyl orarylalkyl). The compound of Formula IV on reaction with benzaldehyde canafford a compound of Formula V, which is a mixture of E & Z isomers. Thecompound of Formula V on subjecting to acylion condensation with4-fluorobenzaldehyde can afford a 1,4 diketo compound of Formula VI. Thecompound of Formula VI on condensation with chiral amine of Formula VIIcan result in a compound of Formula VIII, which on subsequentdeprotection can give a compound of Formula IX. Selective reduction ofcarboxyl group in compound of Formula IX can afford a compound ofFormula X. Acid catalyzed cleavage of the ketal group in compound ofFormula X can result in a dihydroxy compound of Formula XI which can beconverted into calcium salt of the desired Formula I in two ways:

-   -   i) by directly converting the compound of Formula XI into its        hemi calcium salt of Formula I under phase transfer catalysis        using Ca(OH)₂, or    -   ii) by converting the compound of Formula XI to its sodium salt,        generated in situ, using sodium hydroxide and subsequent        displacement of sodium with Ca using calcium acetate or calcium        chloride to generate the hemi calcium salt of Formula I.

The reaction of an amine of Formula II with 4-methyl-3-oxopentanoate canbe carried out in one or more solvents, for example, hydrocarbonsolvents (e.g., hexane, heptane, xylene or toluene, in presence of anorganic base, for example, triethylamine, pyridine or1,2-ethylenediamine in a catalytic amount.

The reaction of a compound of Formula IV with benzaldehyde can becarried out in one or more solvents, for example, hexane, heptane ortoluene, in presence of an organic base, for example, piperidine,pyridine or β-alanine, and an organic acid, for example, glacial aceticacid or benzoic acid.

The reaction of a compound of Formula V with 4-fluorobenzaldehyde can becarried out in presence of a catalyst (e.g., sodium cyanide,3-ethyl-5-(2-hydroxy-ethyl)-4-methyl thiazolium bromide or3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride), in asolvent-free environment, or in a solvent, for example, polar solvent(e.g., methanol, ethanol, propanol or isopropanol), ether solvent (e.g.,dioxane, diethyl ether or tetrahydrofuran) or mixtures thereof, or inpresence of an organic base (e.g., triethylamine or pyridine).Alternatively, the reaction can be carried out in the presence of excessbase, for example, triethylamine which itself acts as a solvent.

The reaction of a compound of Formula VI with a compound of Formula VIIcan be carried out in one or more solvents, for example, hydrocarbonsolvents (e.g., xylene, toluene, hexane or heptane), ether solvents(e.g., tetrahydrofuran or dioxane) or mixtures thereof, in the presenceof an organic acid, for example, pivalic acid or p-toluene sulfonicacid.

The deprotection of a compound of Formula VIII can be carried out attemperatures ranging from about 10° C. to reflux temperature, forexample, at temperatures ranging from about 40 to about 50° C., inpresence of an inorganic base (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate,potassium carbonate, sodium bicarbonate or potassium bicarbonate); inone or more solvents, for example, polar solvents (e.g., methanol,ethanol, acetonitrile, isopropyl alcohol or t-butanol) or ether solvents(e.g., tetrahydrofuran, diethyl ether or dioxane) or mixtures thereof.Alternatively, deprotection can be carried out under phase transfercatalysis using TBAB in aqueous alcoholic solvents, for example, ethanolor methanol at reflux temperatures.

The reduction of a compound of Formula IX can be carried out in presenceof a reducing agent (e.g., boron-dimethylsulfide complex orboron-tetrahydrofuran complex); in one or more solvents, for example,hydrocarbon solvents (e.g., hexane, n-heptane or toluene), ethersolvents (e.g., tetrahydrofuran, dioxane or diethyl ether) or mixturesthereof.

The cleavage of the ketal group of a compound of Formula X with an acid(e.g., hydrochloric acid) can be carried out at temperatures rangingfrom about room temperature (about 25° C.) to reflux temperature,preferably at temperatures ranging from about 40 to about 55° C. in oneor more solvents, for example, polar solvents (e.g., methanol, ethanolor isopropyl alcohol), ether solvents (e.g., tetrahydrofuran, dioxane ordiethyl ether) or combination thereof.

The compound of Formula XI can be converted into its corresponding hemicalcium salt of formula I either:

-   -   i) by first converting Formula XI compound into its sodium salt        by treatment with NaOH at temperature ranging from about 0 to        about 30° C., for example, at temperature ranging from about 0        to about 10° C. and subsequent displacement of sodium with        calcium using calcium acetate in the presence of one or more        alcoholic solvents, for example, methanol, ethanol, etc. or        ether solvents (e.g., tetrahydrofuran, dioxane or diethyl ether)        or combinations thereof, or    -   ii) by subjecting Formula XI compound to phase transfer        catalysis using tetrabutylammonium bromide as the catalyst and        calcium hydroxide as the base in refluxing aqueous alcoholic        solvent, for example, methanol or ethanol.

The process described above may involve one or more of the followingembodiments. For example, the reaction of the compound of Formula II canbe carried out in toluene. The reaction of the compound of Formula V canbe carried out in presence of triethylamine, which itself can act as asolvent. The reaction of the compound of Formula VIII can be carried outin acetonitrile or methanol:tetrahydrofuran (1:3), in presence of sodiumhydroxide at temperatures ranging from about 50 to about 55° C. forabout 4-5 hours or, for example, at about 30° C. for about 8-10 hours.The reaction of the compound of Formula IX can be carried out attemperatures ranging from about 40 to about 45° C. for about 5 hours.The reaction of the compound of Formula X can be carried out inmethanol:tetrahydrofuran:water (1:1:1). The reaction of the compound ofFormula XI can be carried out tetrahydrofuran:de-ionized water (1:1) orethanol:water (4:1), in presence of tetrabutylammonium bromide at atemperature ranging from about 30 to about 50° C. for about 2-8 hours.

The process as enumerated above has an advantage that, none of the stepsinvolve the use of column chromatography as a purification method, thusenables such processes to achieve high yields and makes them amenable tolarge-scale production.

The compound of Formula IV can be purified by dissolving the crudeproduct of Formula IV in ethyl acetate and washing the ethyl acetatelayer successively with an acid then by de-ionized water, the excessacid can be removed by washing the solution successively with sodiumbicarbonate solution, de-ionized water, concentrated to obtain a solid,which can be added to hexane and stirred till the product precipitatesout, which is filtered and dried.

The compound of Formula V can be purified by washing the crude productof Formula V with hexane to remove the organic impurities followed bydrying the product, which can be dissolved in ethyl acetate andpartitioned with de-ionized water to remove the inorganic impurities,the organic layer can be separated, dried and dissolved in isopropylalcohol with heating, which on cooling can give the solid product,filtered and dried in vacuum tray drier at temperatures ranging fromabout 40 to about 50° C. for about 6 hours.

The compound of Formula VI can be purified by dissolving the crudeproduct of Formula VI and activated charcoal in a solvent system ofmethanol and water and refluxing the reaction mixture, filtered and theresidue so obtained can be washed with solvent methanol:water (9:1), thefiltrate can be concentrated to obtain a solid, slurred in hexane,filtered, and concentrated under vacuum.

The compound of Formula VIII can be purified by cooling the reactionmixture to about 0° C. and stirring till the product precipitates, whichcan be filtered, washed with hexane, and dried.

The compound of Formula IX can be purified by a) cooling the reactionmixture to room temperature and acidifying it, filtering to get thesolid and washing it with de-ionized water and acetonitrile, the solidcan be further refluxed in denatured spirit, cool till the productprecipitates out, filtered, washed with denatured spirit, and driedunder vacuum, b) concentrating the reaction mixture and extracting itinto a solvent system of ethyl acetate and water, separating the ethylacetate layer and washing it with brine, the organic layer can befurther acidified wherein, the excess acid can be neutralized by a baseand washed with de-ionized water, the reaction mixture can beconcentrated and the residue can be triturated with hexane to formsolid, filtered, and dried under vacuum.

The compound of Formula X can be purified by a) dissolving the crudeproduct in ethyl acetate and washing the layer successively withde-ionized water, sodium bicarbonate and brine, concentrated to obtain asolid, which can be slurred in hexane, filtered and dried under vacuum,b) dissolving the crude product in the solvent system of isopropylalcohol, de-ionized water and acetic acid, and refluxing it withconcurrent addition of calcium hydroxide, the hot solution can befiltered, the filtrate so obtained can be cooled to room temperaturetill the solid precipitates out, filtered, washed with ice-coldisopropyl alcohol and water, dried in vacuum tray drier at about 60° C.for about 7-8 hours.

The compound of Formula XI can be purified by a) dissolving the crudeproduct in a solvent system of ethyl acetate and toluene (1:2) andwashing the layer successively with de-ionized water and brine, theproduct can be isolated, slurred in hexane at about 40° C. for about 1hour, cooled, filtered and dried in vacuum tray drier at about 60° C.for about 3 hours, b) dissolving the crude product in (10%) ethylacetate-hexane solvent system with concurrent heating at temperaturesranging from about 40 to about 50° C. for about 1 hour, cooled to roomtemperature (about 25° C.) and stirred for about 1 hour or till theproduct precipitates, the solid so obtained can be filtered, washed withwater and hexane and dried in vacuum tray drier.

The compound of Formula I can be purified by a) washing the crudeproduct with ethyl acetate and drying it under vacuum at temperaturesranging from about 60 to about 70° C. for about 10 hours, dissolved inmethanol and to it can be added butylated hydroxy anisole, the solutioncan be filtered to obtain a solid, which can be dried in vacuum traydrier at temperatures ranging from about 40 to about 50° C. to form pureamorphous compound, b) refluxing the crude calcium salt in a solventsystem of ethyl acetate and water (1:1) and butylated hydroxy anisole,the hot solution can be filtered, the filtrate can be cooled till theproduct completely precipitates out, filtered, washed with ethyl acetateand dried under vacuum to form pure amorphous compound, c) filtering thehot reaction mixture, the filtrate so obtained can be cooled and to itcan be added de-ionized water, the product precipitates out, filtered,subjected to reflux in ethyl acetate and water mixture (1:1); thereaction mixture can be cooled till the product precipitates out, whichcan be followed by isolating the product, washing it with ethyl acetateand drying it in vacuum tray drier to form pure amorphous compound.

In the above reaction scheme, where specific reducing agents, solvents,bases, catalysts, acids etc., are mentioned, it is to be understood thatother reducing agents, solvents, bases, catalysts, acids etc., known tothose skilled in the art may be used. Similarly, the reactiontemperature and duration may be adjusted. While the present inventionhas been described in terms of its specific embodiments, certainmodifications and equivalents will be apparent to those skilled in theart and are included within the scope of the present invention.

EXAMPLES Example 1 Preparation of Methyl4-[(4-methyl-3-oxopentanoyl)amino]benzoate of Formula IV

To a solution of methyl-4-aminobenzoate (250 g, 1.65 moles) in toluene(2.4 L) was added methyl-4-methyl-3-oxopentanoate (237.7 g, 1.648 moles)and ethylene diamine (1.15 ml, 0.016 moles). The reaction mixture wasrefluxed for about 20-25 hours. The solvent was removed under reducedpressure to obtain a solid residue. The residue was dissolved in ethylacetate (2.4 L). The organic phase was washed with an acid (e.g., 20%w/w hydrochloric acid 0.5 L) followed by dc-ionized water. It wasfurther washed with a 10% sodium bicarbonate solution, followed byde-ionized water and saturated brine. The solvent was removed underreduced pressure. To this was added hexane while stirring and the solidprecipitated out completely. The solid was filtered and washed withhexane. The solid was dried to yield the title product in 99.45% purity.

Yield: 358 g (1.5, w/w); LCMS: m/z (M+1) 265.09; Melting range: 54-56°C.; ¹H NMR (CDCl₃): δ 1.16-1.18 (d, 6H, —CH(CH ₃)₂), 2.75-2.70 (m, 1H,—CH(CH₃)₂), 3.62 (s, 2H, CH ₂), 3.89 (s, 3H, OCH ₃), 7.62-7.65 (d, 2H,ArH), 7.98-8.01 (d, 2H, ArH), 9.51 (bs, NHCO).

Example 2 Preparation of Methyl4-{[-2-benzylidene-4-methyl-3-oxopentanoyl]amino}benzoate of Formula V

To a mixture of compound of Formula IV (400 g, 1.52 moles) andbenzaldehyde (177 g, 1.67 moles) in hexane (5.4 L) was added β-alanine(27 g, 0.3 moles) followed by glacial acetic acid (54.6 g, 0.91 moles)while under stirring. The reaction mixture was refluxed for about 24hours with constant removal of moisture with the help of a Dean-Starkapparatus. At the end of the reaction, solid precipitated. The solid wasfiltered and washed with hexanes (0.6 L). The solid was dissolved inethyl acetate (3.6 L) followed by addition of de-ionized water (1.2 L)with stirring. The layers were separated and the organic layer waswashed with brine. The solvent was removed under reduced pressure toobtain a solid product, which was dissolved in isopropyl alcohol (0.85L) on heating. The solution was cooled to room temperature and the solidprecipitated. The solid was filtered and successively washed withice-cold isopropyl alcohol and hexanes. The solid was dried under vacuum(10 mbar) at about 40 to about 50° C. for about 6 hours to obtain thedesired product as a mixture of E & Z isomers.

Yield: 338 g (0.84, w/w); LCMS: m/z (M+1) 352.1; Melting range: 154-156°C.; ¹H NMR (CDCl₃):

E isomer δ 1.21-1.23 (d, 6H, —CH(CH ₃)₂), 3.32-3.39 (m, 1H, —CH(CH₃)₂),3.90 (s, 3H, OCH ₃), 7.33-7.39 (m, 3H, ArH), 7.53-7.59 (m, 4H, ArH),7.93 (s, 1H, vinylic H), 8.00-8.02 (d, 2H, ArH). (melting range ofanalytical sample, 155.0-156.2° C.)

Z isomer: δ 1.03-1.05 (d, 6H, —CH(CH ₃)₂), 2.62-2.65 (m, 1H, —CH(CH₃)₂),3.91 (s, 3H, OCH ₃), 7.30-7.32 (m, 2H, ArH), 7.42-7.45 (m, 3H, ArH),7.71-7.73 (d, 2H, ArH), 8.03-8.05 (d, 2H, ArH), 8.21 (s, 1H, vinylic H).(Melting range of analytical sample, 145.6-146.3°C.)

Example 3 Preparation of Methyl4-({2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoyl}amino)benzoateof Formula VI

To a mixture of compound of Formula V (100 g, 0.285 moles) intriethylamine (0.2 Lt) was added thiazolium bromide (17.94 g, 0.071moles) and 4-fluorobenzaldehyde (38.82 g, 0.313 moles). The reactionmixture was subjected to reflux for about 8 hours. At the end of thereaction, as indicated by TLC or reaction monitoring by HPLC,triethylamine was removed under reduced pressure. The solid so obtainedwas dissolved in ethyl acetate (0.75 L) followed by the addition ofde-ionized water (0.25 L). The organic phase was then separated and theaqueous layer was washed with ethyl acetate. The combined organic layerwas washed successively with de-ionized water, acid (e.g., 10%hydrochloric acid 0.2 L), base (e.g., 10% sodium bicarbonate) and brine.The solvent was removed under reduced pressure to obtain a solidproduct. The solid was dissolved in a solvent system of methanol andwater (9:1, 0.75 L) on heating with added activated charcoal (7.5 g) andbrought to reflux. The hot solution was filtered and the residue waswashed with solvent system of methanol and water (9:1). The filtrate wasfurther cooled to about 0 to about 5° C. and the solid that precipitatedwas filtered. The solid was slurred with hexanes (0.4 L) at about 40° C.for 1 hr and was filtered. The product was dried under vacuum (10 mbar)at about 50° C. for about 10 to about 12 hours to give the product ofdesired quality.

Yield: 156 g (0.93, w/w); Melting range: 168.5-170° C.; LCMS: m/z (M+1)476.21 ¹H NMR (CDCl₃): δ 1.15-1.18 (d, 3H, —CH ₃), 1.22-1.25 (d, 3H,—CH₃), 2.96-3.02 (m, 1H, CH(CH₃)₂), 3.89 (s, 3H, —OCH ₃), 4.54-4.56 (d,1H, —CO—CH-Ph), 5.33-5.36 (d, 1H, —CO—CH—CO—), 7.01-7.99 (m, 14H, Ar—Hand —NH).

Example 4 Preparation of Methyl4-({[1-{2-[(4R,6R-6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]ethyl}-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-3-yl]carbonyl}amino)benzoateof Formula VIII

Pivalic acid (44.2 g, 0.433 moles) was added to a mixture of a compoundof Formula VI (200 g, 0.421 moles) and[6-(2-Amino-ethyl)-2,2-dimethyl-[1,3-d]oxan-4-yl]-acetic acid t-butylester of Formula VII (137.9 g, 0.505 moles) in solvent system ofheptane, toluene and tetrahydrofuran in the ratio of 4:1:1 (2.52 L). Thereaction mixture was refluxed for about 28 to about 35 hours. Thereaction mixture was cooled to about 0° C. and stirred till the productprecipitates. The precipitated product was filtered and washed withhexanes (1 L). The solid was dried under vacuum (10 mbar) at about 50°C. to obtain the desired product.

Yield: 210 g (1.05, w/w); LCMS: m/z (M+1) 713.2; Melting range:158.8-159.5° C.; ¹H NMR (CDCl₃): δ 1.03-1.06 (m, 1H, >NCH₂CH ₂—),1.30-1.36 (2×s, 6H, >C(CH ₃)₂ & m, 1H, >NCH₂CH ₂— merged together), 1.43(s, 9H, —C(CH ₃)₃), 1.52-1.54 (d, 6H, —CH(CH ₃)₂), 1.66 (m, 2H, C-5-CH₂—), 2.2-2.4 (m, 2H, —CH2COO^(t)Bu), 3.6 (m, 1H, —CH(CH₃)₂), 3.7 (m, 1H,C-4>CHO—), 3.85 (s, 3H, —OCH ₃), 3.85 (m, 1H, C-6>CHO—), 4.1 (m, 2H,>NCH ₂—), 6.97-7.85 (m, 14H, Ar—H and —NH).

Example 5 Preparation of4-({[1-{2-[(4R,6R)-6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]ethyl}-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-3-yl]carbonyl}amino)benzoicacid of Formula IX

Sodium hydroxide (2.5 molar equiv., 1N aq. soln.) was added to asolution of compound of Formula VIII (425 g, 0.596 moles) inacetonitrile (4.25 L) and the reaction mixture was stirred at about50-55° C. for about 4-5 hours. The reaction mixture was cooled to about25° C. and the pH adjusted to 5.5-6 with 20% acetic acid solution whenthe product precipitated out. The solid was then filtered and washedwith de-ionized water and acetonitrile. The crude product obtained wasrefluxed in denatured spirit (7.2 L) for about 1 hour. The reactionmixture was cooled to about 25° C. and stirred for about 5 hours tillthe solid precipitated completely. The solid was filtered and washedwith denatured spirit (0.42 L). The solid was further dried under vacuum(10 mbar) at about 50° C. for about 6 hours to obtain the desiredproduct.

Yield: 324.95 g (0.76, w/w); LCMS: m/z (M+1) 699.3; Melting range:239.9-241.7° C.; ¹H NMR (CDCl₃): δ 1.03-1.06 (m, 1H, >NCH₂CH ₂—),1.30-1.36 (2×s, 6H, >C(CH ₃)₂ & m, 1H, >NCH₂CH ₂— merged together), 1.43(s, 9H, —C(CH ₃)₃), 1.52-1.54 (d, 6H, —CH(CH ₃)₂), 1.64-1.68 (m, 2H,C-5-CH ₂—), 2.2-2.4 (m, 2H, —CH ₂COO^(t)Bu), 3.6 (m, 1H, —CH(CH₃)₂), 3.7(m, 1H, C-4>CHO—), 3.8 (m, 1H, C-6>CHO—), 4.15-4.17 (m, 2H, >NCH ₂—),6.97-7.92 (m, 14H, ArH and —NH).

Alternatively, sodium hydroxide (2.5 eq., 1N aq. soln.) was added to asolution of compound of Formula VIII (100 g, 0.14 moles) in a mixture oftetrahydrofuran and methanol (1.0 L, 3:1) and the reaction mixture wasstirred at room temperature (30° C.) for about 8-10 hours. Thevolatilities were distilled at reduced pressure and ethyl acetate andwater (1:1) charged under stirring at room temperature. The organicphase was separated and washed with saturated brine; any insolublematerial that precipitated was filtered. The pH of the organic phase wasadjusted to 5.5-6 with 20% acetic acid solution and subsequently washedwith de-ionized water and bicarbonate solution. The organic volatilitieswere removed under reduced pressure and the residue was triturated withhexanes to give the solid, which was filtered and washed with hexanes.The solid was further dried under vacuum (10 mbar) at about 50° C. forabout 6 hours to obtain the desired product.

Yield: 60 g (0.6, w/w).

Example 6 Preparation oftert-butyl((4R,6R)-6-{2-[2-(4-fluorophenyl)-4-({[4-(hydroxymethyl)phenyl]amino}carbonyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxan-4-yl)acetateof Formula X

A solution of a compound of Formula IX (100 g, 0.14 moles) intetrahydrofuran (0.7 L) was heated to about 40-45° C. To it was addedboron-dimethyl sulfide complex (BMS complex 2.3 eq., 2M soln. intetrahydrofuran). The reaction mixture was stirred at this sametemperature for about 5 hours. The reaction mixture was cooled to about20-25° C. and to it was added methanol to destroy excess BMS complex.The organic volatilities were removed under vacuum and the residue soobtained was dissolved in ethyl acetate. The organic phase wassuccessively washed with de-ionized water, sodium bicarbonate and brine.On distilling the solvent under reduced pressure (10 mbar) at 50° C. thedesired product obtained was a solid. The solid reaction mass wasslurred in hexanes and filtered. The product so obtained was dried undervacuum (10 mbar) at about 60° C. for about 7-8 hours and used for thenext step.

Yield: 95 g, (0.95, w/w); LCMS: m/z (M+1) 685.3; Melting range:193.8-194.6° C.; ¹H NMR (CDCl₃): δ 1.03-1.06 (m, 1H, >NCH₂CH ₂—),1.30-1.36 (2×s, 6H, >C(CH ₃)₂ & m, 1H, >NCH₂CH ₂— merged together), 1.43(s, 9H, —C(CH ₃)₃), 1.52-1.54 (d, 6H, —CH(CH ₃)₂), 1.66-1.67 (m, 2H,C-5-CH ₂—), 2.2-2.4 (m, 2H, —CH ₂COO^(t)Bu), 3.58 (m, 1H, —CH(CH₃)₂),3.68 (m, 1H, C-6>CHO—), 3.82 (m, 1H, C-4>CHO—), 4.07-4.17 (m, 2H, >NCH₂—), 4.57 (s, 2H, —PhCH ₂OH), 6.87-7.21 (m, 14H, ArH and —NH).

Alternatively, the reaction mixture after quenching with methanol todestroy the excess BMS complex is subjected to distillation underreduced pressure to reduce the volatiles to a minimum and allowed toattain ambient temperature. Acetic acid was added to the reactionmixture along with isopropyl alcohol and de-ionized water. The reactionmixture was heated to reflux and calcium hydroxide charged. The reactionmixture was filtered hot and the filtrate on cooling to 20-25° C.results in the precipitation of the solid product, which was filteredand washed with a mixture of chilled isopropyl alcohol and water. Theproduct so obtained was dried under vacuum (10 mbar) at 60° C. for 7-8hours and the desired product, so obtained was used for the next step.

Example 7 Preparation of(3R,5R)-7-[2-(4-fluorophenyl)-4-({[4-(hydroxymethyl)phenyl]amino}carbonyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid t-butyl ester of Formula XI

Hydrochloric acid (1N, aq soln.) was added to a solution of a compoundof Formula X (25 g, 0.036 moles) in a solvent system of methanol andtetrahydrofuran (1:1), 0.125 L at room temperature. The reaction mixturewas stirred for about 5 hours or till the completion of the reaction.The reaction mixture was quenched with sodium bicarbonate (1.53 g, 0.018moles) and subjected to removal of the organic volatilities underreduced pressure. The residue so obtained was taken up in ethyl acetateand toluene (1:2, 0.5 L). The organic phase was washed successively withde-ionized water and brine. Removal of the solvent under vacuum resultedin a solid product. The solid obtained was slurred in hexane at about40° C. for about 1 hour, followed by cooling to ˜25° C. and filtration.The solid obtained was dried under vacuum (20 mm) at about 60° C. forabout 3 hours.

Yield: 22 g, (0.88, w/w); LCMS: m/z (M+1) 645.2; Melting range:144.6-146.1° C.; ¹H NMR (CDCl₃): δ 1.20-1.24 (m, 1H, >NCH₂CH ₂—),1.40-1.45 (s, 9H, —C(CH ₃)₃ & m, 1H, >NCH₂CH ₂— merged together),1.52-1.54 (d, 6H, —CH(CH ₃)₂), 1.62 (m, 2H, C-4 CH ₂(—CHOH)₂), 2.3-2.32(d, 2H, —CH ₂COO^(t)Bu), 3.56-3.59 (m, 1H, —CH(CH₃)₂), 3.72 (bs, 2H,2xOH), 3.78 (m, 1H, C-5>CHOH), 3.93 (m, 1H, C-3>CHOH), 4.07-4.14 (m, 2H,>NCH ₂—), 4.57 (s, 2H, -PhCH ₂OH), 6.87-7.19 (m, 14H, ArH and —NH).

Alternatively, the compound of formula X (200 g, 0.29 moles) on beingsubjected to acid hydrolysis in a mixture oftetrahydrofuran:methanol:water (1:1:1, 3 Lt) at about 50° C. in presenceof 1N HCl (0.5, molar equiv.) for about 1-2 hours afforded the desiredcompound in solution. The reaction mixture was quenched with sodiumbicarbonate (15.96 g, 0.19 moles) and the organic volatiles weredistilled leaving behind 50% of the total reaction volume. To thereaction mixture was added 10% ethyl acetate in hexanes (2 L) andsubjected to a temperature of about 40-50° C. for about 1 hour. Thereaction mixture was then cooled to ˜25° C. and stirred at thistemperature for about 1 hour for complete precipitation. The product soobtained was filtered and washed with water (0.2 L) and hexanes (0.4 L).The solid obtained was dried under vacuum (20 mm) at about 60° C. forabout 3 hours. Yield: 0.87 (w/w).

Example 8 Preparation of(3R,5R)-7-[2-(4-fluorophenyl)-4-({[4-(hydroxymethyl)phenyl]amino}carbonl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoicacid hemi calcium salt of Formula I

A solution of a compound of Formula XI (60 g, 0.093 moles) in methanoland tetrahydrofuran (1:1, 0.3 L) was stirred at room temperature. Thereaction mixture was cooled to 0° C. A solution of sodium hydroxide (1Naq. soln., 1.2 eq.) was added to the reaction mixture and thetemperature was not allowed to exceed 10° C. during addition. Thereaction mixture was stirred for about 3 hours at about 5-10° C. Thesolvent was then removed under reduced pressure. The solid productobtained was dissolved in ethyl acetate (0.3 L); to it was addedde-ionized water (0.6 L). The aqueous layer containing the desiredproduct was separated and washed with ethyl acetate. To this aqueouslayer was added calcium acetate solution (0.66 L, 0.6 eq.) and stirredtill product of Formula I precipitated. The product was filtered andwashed with ethyl acetate. The product was dried under vacuum (10 mm) at60-70° C. for about 10 hours. The product obtained above (50 g, yield0.833, w/w) was dissolved in methanol (0.245 L) and butylated hydroxyanisole (BHA, 0.05 m01%) was added. The solution so obtained wasfiltered and evaporated to dryness under vacuum (10 mm) at 40-50° C. toget the desired amorphous form of the compound of Formula I (44 g).

Over all yield: 44 g, (0.73, w/w); LCMS: m/z (M+1) 589.1; ¹H NMR(CD₃OD): δ 1.36-1.39 (m, 1H, C-6>NCH₂CH ₂), 1.46-1.47 (d, 6H, CH(CH₃)₂), 1.51-1.53 (m, 1H, C-6>NCH₂CH ₂ merged with CH(CH ₃)₂), 1.67-1.68(m, 2H, C-4 CH ₂(—CHOH)₂) 2.22-2.32 (m, 2H, C-2-CH ₂COO⁻), 3.33-3.37 (m,1H, CH(CH₃)₂), 3.64-3.65 (m, 1H, C-5>CHOH), 3.89 (m, 1H, C-3>CHOH),3.99-4.06 (m, 2H, C-7>NCH ₂—), 4.51 (s, 2H, -PhCH ₂OH), 7.02-7.12 (m,7H, ArH), 7.20-7.24 (m, 4H, ArH), 7.27-7.29 (m, 2H, ArH).

Alternatively, the compound of Formula XI (80 g, 0.124 moles) intetrahydrofuran and deionized water (1:1, 0.8 L) was stirred at roomtemperature in the presence of sodium hydroxide (1N aq sol, 1.2 eq.) forabout 2-3 hours at about 30° C. The solvent tetrahydrofuran was thenremoved under reduced pressure and the residue taken up in ethyl acetatewater mixture. The aqueous layer containing the desired product wasseparated and washed with ethyl acetate. To this aqueous layer was addedcalcium acetate (0.6 eq.) under stirring. The desired productprecipitated. To the precipitated product in aqueous solution was addedethyl acetate such that the ratio of ethyl acetate and water is 1:1 andbutylated hydroxyl anisole (0.05 mol %) and the reaction mixture wasrefluxed to dissolve the solids. The hot solution was filtered andallowed to cool to room temperature (25-30° C.) under stirring when thedesired Ca-salt of compound of Formula I precipitated. The product wasfiltered and washed with ethyl acetate. The product was dried undervacuum (10 mm) at 55-65° C. for 10-12 hours, (yield, 60 g, 0.75 w/w).The desired compound of Formula I, was obtained above, and was treatedfurther to produce one single morph consistently, i.e., the amorphousform of compound of Formula I. Thus, to a solution of the compound ofFormula I (25 g) in methanol (500 ml) was added butylated hydroxylanisole (0.05 mol %), filtered and subjected to spray drying techniqueto give the desired amorphous form (20.5 g).

Yield: 0.82 w/w; Overall yield: 0.61

Alternatively, a mixture of compound of Formula XI (80 gms, 0.124moles), calcium hydroxide (13.8 g, 0.186 moles) and tetrabutylammoniumbromide (2 g, 5 mol %) in ethanol:water mixture (4:1, 0.8 L) was heatedto about 50° C. for about 5-8 hours under stirring. Reaction mixtureshows consumption of the starting material as indicated by TLC or byHPLC. The reaction mixture was filtered hot (˜50° C.). The filtrate wascooled to room temperature (˜25° C.) and charged to deionized water (2.4L) under stirring. The precipitated product was filtered and washed withwater (0.16 L) and sucked dry. The wet cake was refluxed in ethylacetate:water mixture (1:1, 1.6 L) till the complete dissolution ofsolids. The reaction mixture was cooled to 25° C. under stirring forabout 2 hours to afford the compound of Formula I of desired quality.The solid was filtered and washed with ethyl acetate (0.32 L), suckeddry and further dried under the above conditions, yield, 50.5 g (0.63,w/w). Further treatment of the product as described above affords theamorphous compound of Formula I.

1. A method of making 3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methylphenyl amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates,polymorphs, pro-drugs, stereoisomers, tautomeric forms, N-oxides andmetabolites thereof, the method comprising: (a) reacting a compound ofFormula II with a compound of Formula III,

to form a compound of Formula of IV (wherein R is alkyl, aryl orarylalkyl);

(b) reacting the compound of Formula IV with benzaldehyde to form acompound of Formula V;

(c) reacting the compound of Formula V with 4-fluorobenzaldehyde to forma compound of Formula VI;

(d) reacting the compound of Formula VI with a compound of Formula VII,

to form the compound of Formula VIII;

(e) deprotecting the compound of Formula VIII to form a compound ofFormula IX;

(f) reducing the compound of Formula IX to form a compound of Formula X;

(g) deprotecting the compound of Formula X to form a compound of FormulaXI; and

(h) converting the compound of Formula XI to compound of Formula I,wherein any purification of products of the steps (a) to (h) is carriedout without using column chromatography, and the reaction in step (h)involves a one-pot conversion of compound of Formula XI to the calciumsalt of Formula I.
 2. The process according to claim 1, wherein step (a)involves reaction in toluene.
 3. The process according to claim 1,wherein step (c) involves triethylamine.
 4. The process according toclaim 1, wherein the reaction of step (e) is carried out in one or moresolvents selected from acetonitrile, propionitrile, dimethylsulfoxide,dimethylformamide and dimethoxyethane or methanol:tetrahydrofuran (1:3),in presence of sodium hydroxide, at temperatures ranging from about 50to about 55° C. for about 4-5 hours, or at about 30° C. for about 8-10hours.
 5. The process according to claim 1, wherein the step (f) iscarried out at a temperatures ranging from about 40 to about 45° C. forabout 5 hours.
 6. The process according to claim 1, wherein the reactionof step (g) is carried out in methanol:tetrahydrofuran:water (1:1:1). 7.The process according to claim 1, wherein the reaction of step (h) iscarried out in tetrahydrofuran:de-ionized water (1:1).
 8. The processaccording to claim 1, wherein the reaction of step (h) is carried out inethanol:water (4:1) in presence of calcium hydroxide and a phasetransfer catalyst selected from tetraalkylammonium halide,tetrabutylammonium hydrogen sulfate, tetrabutylammonium thiocyanate,tetrabutylammonium tetrafluoroborate, benzyltributylammonium chlorideand tetraalkylphosphonium halide.
 9. The process according to claim 1,wherein the reaction of step (h) is carried out at a temperature rangingfrom about 30 to about 50° C. for about 2 to about 8 hours.
 10. Theprocess according to claim 1, wherein the product of step (h) isamorphous.